Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/795—Polymers containing sulfur
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
  • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• This invention relates to solid dosage forms of the antiarrhythmic drug almokalant (p-INN) formulated as immediate release (IR) tablets and extended release (ER) tablets as well as processes for manufacture thereof.
• p-INN antiarrhythmic drug almokalant
• the invention relates to the use of the polystyrene sulphonate complex of almokalant in solid dosage forms.
• Almokalant (p-INN), 4-[3-[ethyl[3-(propylsulfinyl)- propyl]amino]-2-hydroxypropoxy]-benzonitrile free base is a viscous, sticky substance, problematic to handle in the manufacture of solid dosage forms. It has a pronounced tendency to give a repellent odorous degradation product with a smell resembling old onions.
• the aim of the present invention is to provide solid dosage forms of the antiarrhythmic drug almokalant, formulated as IR-tablets and ER-tablets with improved stability and minimal odour.
• ER-tablets can be formulated by a variety of formulation principles, such as for instance hydrophilic gel-matrix tablets, matrix tablets, membrane diffusion controlled formulations, osmotic pressure controlled dosage forms etc.
• formulation principles such as for instance hydrophilic gel-matrix tablets, matrix tablets, membrane diffusion controlled formulations, osmotic pressure controlled dosage forms etc.
• almokalant polystyrene sulphonate complex (A-PSS) , had a much better stability, less repelling odour and was much easier to handle in tablet manufacture.
• ER tablets it is necessary to mix the formed complex with e.g. a hydrophilic matrix. It is especially preferable to use hydroxypropyl methylcellulose as the ge forming substance. It is further preferred to use a mixture of HPMC containing both low and high molecular weight HPMC.
• Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 85 parts, microcrystalline cellulose 91 parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
• a reference preparation was produced by dissolving the free base in a 2M hydrochloric acid solution and using this solution to granulate the excipients.
• the A-PSS tablet was prepared by first mixing ingredients 1 and 2. The mixture was granulated with 3. After drying and milling 4 was admixed, whereupon compression to tablets was performed on a Korsch Pharmapress 100.
• the reference tablet (Ref. ex. I) was prepared by making a granulating solution of the ingredients 1 and 3. The powders in 2 were mixed and then granulated with the prepared solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets compressed on the same machine.
• Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 85 parts, microcrystalline cellulose 91 parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water. After drying the granulate was milled and then mixed with the lubricant sodium stearyl fumarate whereupon compression to tablets was done.
• a reference preparation (Ref. ex. II) was produced by dissolving the free base in an aqueous tartaric acid solution and using this solution to granulate the excipients.
• Lactose pwd 84.5 Lactose anhydrous Avicel ® PH 101 Polyvidone K-25 3.
• Water, purified Tartaric acid 4.
• the A-PSS tablets were prepared by first mixing ingredients 1 and 2. The mixture was granulated with 3. After drying and milling 4 was admixed, whereupon compression to tablets were performed on a Korsch Pharmapress 100.
• the reference tablet (Ref. ex. II) was prepared by making a granulating solution of 1 and 3. The powders 2 were mixed and granulated with the solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets were compressed on the same machine.
• the odour intensity of the two formulations were compared immediately after manufacturing and after 1 month of storage in glass bottles .
• Immediate release tablets of almokalant can be prepared in suitable strengths.
• the A-PSS tablets were prepared by first mixing the ingredients 1. The mixture was granulated with a solution made of ingredients 2. After drying and milling ingredients 3 were admixed, whereupon compression to tablets were performed on a Korsch Pharmapress 100.
• Disintegration (without discs): 0.6-1.0 min. 0.2-0.4 min.
• Extended release tablets of almokalant were prepared by mixing A-PSS 95 parts, hydroxypropyl methylcellulose (HPMC) 50 cps 40 parts, HPMC 10000 cps 160 parts and hydroxypropyl cellulose (HPC) 50 parts and then granulating the mixture with ethanol 99.5%. After drying the granulate was milled and then mixed with sodium stearyl fumarate whereupon compression to tablets was done.
• HPMC hydroxypropyl methylcellulose
• HPMC 10000 cps 160 parts HPMC 10000 cps 160 parts
• HPPC hydroxypropyl cellulose
• a reference preparation (Ref. ex. Ill) was made by dissolving the free base in ethanol (99.5%) and using this solution to granulate the dry excipients, and otherwise following the same way of production.
• HPMC 50 cps (Metolose ® 60SH50) 40.0 40.0 3 .
• HPMC 10000 cps (Methocel ® ⁇ E10MCR) 4.
• H HPPCC LLFF (KKlluuccee:l ® LF) 5. Ethanol 99. 5% 6.
• Sodium stearyl fumarate (Pruv ®*)
• Tablets made using the free base have inferior binding properties.
• the release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle, 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
• Extended release tablets of almokalant can be prepared in suitable strengths and with different release rates.
• Lactose pwd HPMC 50 cps (Metolose ® 60SH50)
• HPMC lOOOOcps (Methocel ® E10MCR)
• HPC LF (Klucel ® LF)
• Polyethylene glycol 20M (Carbowax ® 20M) 30.0
• Polyethylene glycol 6000 (Carbowax ® 6000) 42.0
• Compression to tablets was performed on a Korsch Pharmapress 100.
• the tablet machine was equipped with compression force registration.
• the release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
• Controlled release tablets were prepared by granulating 54.3 parts active substance, 30.0 parts mannitol, 154 parts HPMC 50 cps, 221 parts HPMC 10,000 cps, 37.5 parts HPC, 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Ex. 6) or PVP K-25 (Ex. 7) dissolved in 105 parts of water.
• the dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate.
• HPMC Methodolose ® 60SH50
• HPMC Methodoel ® E10MCR
• Tablet weight 545 mg 545 mg compression force (kN) : tablet hardness (kP):
• the release rate was determined in USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
• almokalant free base in pharmaceutical formulation apart from the inconvenience of handling a sticky, viscous substance - results in dosage forms with inferior stability and palatability as well as in inferior technical properties.
• almokalant polystyrene sulphonate complex in pharmaceutical formulation eases the handling and results in more stabile and more palatable dosage forms.

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• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Chemical Treatment Of Metals (AREA)

Priority Applications (5)

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Publications (1)

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Citations (2)

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• 1990
  • 1990-12-07 SE SE9003902A patent/SE9003902D0/xx unknown
• 1991
  • 1991-11-22 ZA ZA919264A patent/ZA919264B/xx unknown
  • 1991-11-25 IL IL100150A patent/IL100150A0/xx unknown
  • 1991-11-25 TW TW080109239A patent/TW215057B/zh active
  • 1991-11-26 NZ NZ240731A patent/NZ240731A/en unknown
  • 1991-11-27 YU YU186891A patent/YU186891A/sh unknown
  • 1991-11-28 IE IE413791A patent/IE914137A1/en unknown
  • 1991-12-02 AP APAP/P/1991/000338A patent/AP258A/en active
  • 1991-12-02 MX MX9102325A patent/MX9102325A/es unknown
  • 1991-12-03 SK SK55693A patent/SK55693A3/sk unknown
  • 1991-12-03 CA CA002097178A patent/CA2097178A1/en not_active Abandoned
  • 1991-12-03 WO PCT/SE1991/000815 patent/WO1992010172A1/en not_active Application Discontinuation
  • 1991-12-03 CZ CS931037A patent/CZ103793A3/cs unknown
  • 1991-12-03 EP EP91920708A patent/EP0560821A1/en not_active Withdrawn
  • 1991-12-03 HU HU9301670A patent/HUT64217A/hu unknown
  • 1991-12-03 JP JP4500117A patent/JPH06503312A/ja active Pending
  • 1991-12-03 AU AU89307/91A patent/AU8930791A/en not_active Abandoned
  • 1991-12-03 MA MA22639A patent/MA22355A1/fr unknown
  • 1991-12-06 MY MYPI91002267A patent/MY106776A/en unknown
  • 1991-12-06 IS IS3788A patent/IS3788A7/is unknown
  • 1991-12-06 TN TNTNSN91117A patent/TNSN91117A1/fr unknown
  • 1991-12-06 PT PT99719A patent/PT99719A/pt not_active Application Discontinuation
  • 1991-12-07 CN CN91112789A patent/CN1063039A/zh active Pending
• 1993
  • 1993-06-04 FI FI932554A patent/FI932554A/fi not_active Application Discontinuation
  • 1993-06-04 BG BG97851A patent/BG97851A/xx unknown
  • 1993-12-30 LT LTIP1717A patent/LTIP1717A/xx not_active Application Discontinuation

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